Desmosomal Cadherin Cleavage in the Regulation of Apoptosis in the Context of Inflammation Open Access

Yulis, Mark (Spring 2018)

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The regulation of apoptosis sensitivity is critical to the maintenance of physiological homeostasis and dysregulation of apoptosis is known to be involved in the pathobiology or progression of many disease states.  The single pass, transmembrane proteins of the cadherin family have been appreciated as important proteins that regulate intercellular adhesion. In addition to this critical function, cadherins contribute to important signaling events that control cellular homeostasis. Much of the work on cadherin mediated signaling focuses on classical cadherins or on specific disease states such as pemphigus vulgaris. Cadherin mediated signaling has been shown to play critical roles during development, in proliferation, apoptosis, disease pathobiology and beyond.  We have previously reported that select pro-inflammatory cytokines induce ectodomain cleavage of the desmosomal cadherin desmoglein-2 (Dsg2) and shedding of the resulting extracellular fragment from intestinal epithelial cells (IECs).  The Dsg2 extracellular cleaved fragment (Dsg2 ECF) functions to induce paracrine pro-proliferative signaling in epithelial cells.  The goal of this study was to further understand the role of desmoglein cleavage in the regulation of enterocyte homeostasis.  To address this, we focused on characterizing Dsg2 intracellular cleavage and the functional effects of the resultant intracellular cleaved fragment.  In this study, we showed that exposure of IECs to pro-inflammatory cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) resulted in Dsg2 intracellular cleavage and generation of a ~55kDa fragment (Dsg2 ICF).  Dsg2 intracellular cleavage is mediated by caspase-8 and occurs prior to Dsg2 extracellular cleavage and the execution of apoptosis.  Expression of exogenous Dsg2 ICF in model IECs increased sensitivity to apoptotic stimuli and apoptosis execution.  Additionally, expression of the Dsg2 ICF repressed the anti-apoptotic Bcl-2 family member proteins Bcl-XL and Mcl1.  Taken together, our findings identify a novel mechanism by which pro-inflammatory mediators induce cleavage of Dsg2 to activate apoptosis and eliminate damaged cells, while also promoting release of Dsg2 ECF that enhances proliferation of neighboring cells and epithelial barrier recovery.  These findings expand our understanding of the signaling capabilities of desmosomal cadherins and provide a new pathway through which apoptosis can be altered in the context of intestinal inflammation.

Table of Contents

Chapter 1: Introduction                                                                              1

Mechanisms and pathways of apoptosis                                                  2

Regulation of apoptosis sensitivity by the Bcl-2 family of proteins        6

Desmosomal junctions                                                                             7

Overview of Cadherins as Signaling Mediators                                      7

Cadherin mediated regulation of proliferation                                        8

Cadherin mediated modulation of apoptosis                                          11

Cadherin mediated control of cellular differentiation                            12

Other signaling mediated by cadherins                                                  14

Cadherin mediated signaling in the context of disease                          16

Cadherin intracellular fragment mediated signaling                              20

Cadherin signaling in cells lacking intercellular adhesion                     21

The importance of epithelial apoptosis in Inflammatory

Bowel Disease (IBD) pathogenesis                                                        22

Scope and significance of dissertation                                                    24

Figures and table                                                                                     26


Chapter 2: Desmosomal Cadherin Cleavage and Modulation of

Enterocyte Apoptosis in the Context of Inflammation                            38

Introduction                                                                                             39

Results                                                                                                     41

TNF-α and IFN-γ promote Dsg2 Intracellular Cleavage                 41

Calpain Inhibition Leads to Accumulation of Active Caspase-8

and Promotes Dsg2 ICF Generation                                                43

Caspase-8 is Responsible for Generating the Dsg2 ICF                  44

TRAIL promotes Dsg2 cleavage analogous to TNF-α and IFN-γ    45

Expression of the Dsg2 ICF sensitizes epithelial cells to

Apoptosis                                                                                          45

Discussion                                                                                              47

Figures                                                                                                   53

Experimental procedures                                                                       65


Chapter 3: Discussion                                                                                71

A model for Dsg2 cleavage as a beneficial signaling mechanism

during inflammation                                                                               73

Dependency of Dsg2 ECF generation on Dsg2 ICF generation            75

Mechanistic basis for Dsg2 ICF signaling                                             75

The implications of cadherin intracellular fragments as independent

signaling mediators                                                                                80

Additional functions of Dsg2 ICF signaling                                          81

The role of inflammation in Dsg2 cleavage                                           83

Dsg2 cleavage during intrinsic apoptosis                                               84

Placing the Dsg2 ICF and its signaling functions into the broader

context of cadherin mediated signaling                                                  85

Final conclusions                                                                                    87


References                                                                                                   88

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